Recently, development on medicaments have been carried out, which use bio-related substances such as intercellular signaling substances such as hormones and cytokines, antibodies, and enzymes. When injected to a living body, these bio-related substances are usually cleared from the body because of the filtration through glomeruli in the kidney and the uptake by macrophages in the liver, spleen, and the like. Therefore, they have short half-lives in blood and hence it is difficult to obtain a sufficient pharmacological effect. For solving the problems, it is attempted to encapsulate the bio-related substances in liposomes or polymer micelles and to chemically modify the bio-related substances with an amphiphatic polymer such as a sugar chain or polyethylene glycol or albumin. By these attempts, the behavior of the bio-related substances in a living body is improved through increase in their molecular weight or formation of a hydration layer. Moreover, it is also known that effects of decreasing toxicity and antigenicity and enhancing solubility of sparingly water-soluble pharmaceuticals are obtained by the modification with polyoxyethylene.
Non-Patent Documents 1 and 2 have report that there is a case of an ABC (accelerated blood clearance) phenomenon in which half-lives in blood decrease at the second or later administration as compared with the case at the first administration when liposomes or nano particles modified with polyoxyethylene are repeatedly administrated to the same individual. It is considered that this is because an antibody to the polyoxyethylene with which the liposomes or nano particles have been modified is expressed and it is said that the antibody recognizes various sites, such as a terminal end of the polyoxyethylene chain and a repeating structure of the polyoxyethylene. On the other hand, there is a reported example that liposomes and nano particles modified with some hydrophilic polymers such as polyglycerin hardly induce the ABC phenomenon. However, with hydrophilic polymers other than the polyoxyethylene, a sufficient circulation in blood cannot be obtained and also the polymers are poor in examples in clinical use, so that they are not sufficient as alternatives of polyoxyethylene.
On the other hand, in Patent Document 1, there is a description relating to a bio-related substance modified with a polyoxyethylene derivative having one hydroxyl group at a terminal end thereof. When a polyoxyethylene derivative having a hydroxyl group at a terminal end thereof is used, data showing decreased antigenicity are obtained as compared with the case of a polyoxyethylene derivative having a alkoxy group at a terminal end thereof. Such placement of the hydroxyl group at the terminal end of the polyoxyethylene derivative is considered to be one remedial measure for contributing a decrease in antigenicity of polyoxyethylene. However, since the polyoxyethylene derivative described in the document is purified using a reverse-phase chromatography, the yield decreases to a large extent and hence the derivative is not suitable for industrial production. Moreover, in recent years, development of pharmaceutical agents showing more improved circulation in blood has been in progress and there is a need for further decreasing antigenicity.
Since the placement of plural hydroxyl groups at a terminal end of polyoxyethylene leads to formation of a stronger and larger hydrated layer around a carrier, it is considered that the interaction with an opsonin is lowered and, as a result, the antigenicity can be further decreased. There are the following documents on polyoxyethylene having plural hydroxyl groups.
In many documents including Patent Documents 2 and 3, there are descriptions relating to targeting-type preparations wherein a monosaccharide or polysaccharide having plural hydroxyl groups is introduced into a terminal end of a hydrophilic polymer and a drug is bonded thereto. However, the saccharides are used for getting a targeting property through a carbohydrate recognition mechanism present in a living body and it is not intended to improve antigenicity.
Patent Documents 4 and 5 describes hydrophobic polyoxyalkylene having a polyglycerin derivative with a large number of hydroxyl groups. Such hydrophobic polyoxyalkylene is a surfactant which utilizes the hydrophilicity of polyglycerin. In these documents, only examples of hydrophobic polyoxyalkylene are shown and it is difficult to obtain a highly pure polyoxyethylene derivative suitable for modifying bio-related substances by the production methods described therein.
Patent Document 6 describes a copolymer of polyoxyethylene and polyglycidol. In the method of manufacturing a random or block polymer described in the document, the polyglycidol is converted into branched polymers having plural branches and into a mixture of polymers having various structures. As a raw material for medicaments, a highly pure compound having a single structure is required and a mixture is not preferred. Furthermore, it is necessary for a mixture to define a compositional ratio and the like of components contained therein at application for registration of pharmaceutical raw materials and thus much difficulty exists. Moreover, it is difficult to control the number of hydroxyl groups in the polymer at the polymerization of glycidol and hence there is a problem that viscosity of a polymer solution increases when the number of hydroxyl groups increases.
As above, it is a current situation that a polyoxyethylene derivative suitable for modification of bio-related substances, having plural hydroxyl groups that can improve half-lives in blood and antigenicity at one terminal end, and capable of industrial production has not been obtained.